Elastin is an extracellular protein whose intrinsic ability to passively expand and contract under gas and liquid pressure gradients renders it an important functional element in maintaining proper pulmonary function. In pulmonary obstructive diseases such as emphysema, the continual loss of elastin from alveolar walls concomitant with enlargement of air spaces is a significant factor in the pathological process. Evidence obtained from both in vitro and in vivo models of elastase injury demonstrate that insoluble elastin is increased and elastin mRNA levels are up-regulated after elastase damage. Preliminary data supplied show that intratracheal administration of elastase to mice carrying the elastin promoter transgene results in an increase in elastin promoter activity as well as an increase in elastin mRNA levels. The overall objective of this project is to elucidate the mechanisms underlying up-regulation of elastin gene transcription and examine these mechanisms in elastase- induced elastin repair. Our hypothesis is that elastase-induced degradation dependent on their proximity to elastase injury. Published data show that two cis-acting elements (NF1 and Sp1/Sp3 sites) within the elastin gene promoter modulate increases in elastin transcription. Both of these areas are implicated in the up-regulation of elastin gene expression seen in the transition from proliferative to arrested pulmonary fibroblasts and smooth muscle cells and in elastase treated pulmonary fibroblasts smooth muscle cells. Four specific aims are proposed to address the overall hypothesis. 1. Determine the mechanisms involved in the up-regulation of elastin gene expression in pulmonary elastogenic cells. 2. Identify genes that modulate elastin transcription in untreated and elastase treated cell cultures. 3. Characterized the response of pulmonary fibroblasts and smooth muscle cells to localized delivery of elastase. 4. Determine the response of the elastin gene promoter to elastase-induced lung injury in vivo. Overall these studies should provide important information concerning the cis-elements and trans- acting factors that regulate elastin gene transcription and their role in repair responses. Further, the elucidation of transcriptional mechanisms should provide strategies for Treatment in early stages of COPD where the re-synthesis of elastin may be critical event in determining the progression of the disease.